History of Vaccines 8667

8/8/2019 History of Vaccines 8667

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History of Vaccines

Leading cause of death in human population INFECTION

Most important contributions to public

health in last 100 yrs

SANITATION

VACCINATION

Earliest contributions

JENNER ± smallpox vaccine PASTEUR ± rabies vaccine

Greatest Triumphs

Global eradication of smallpox (1980)

Future global eradication of polio



HistoryHistory

Although early in history the basis of disease was not known, the presence of a

life-long immunity to disease was understood as early as the 4th century.

The first documentation of ³immunization´ was the process of variolation ± the

removal of pus from smallpox lesions and the subsequent scratching of an

uninfected person in the 10th

century in India In 1796, Edward Jenner observed that milk maids exposed to cowpox (vaccinia

virus) did not acquire smallpox ± he predicted that deliberately infecting an

individual with vaccinia would protect against smallpox (variola virus) ± Sarah

Nelmes donated fluid from her cowpox-infected hands, which was inoculated

into James Phipps ± produced a lesion similar to cowpox ± later challenged

James Phipps with fluid from a smallpox lesion, but no subsequent smallpox

developed ± this was the first recorded incidence of ³vaccination´.

Jenner would be imprisoned for this type of experiment today, but the James

Phipps vaccination led to the development of the smallpox vaccine and the

eradication of naturally occurring infections worldwide.







Immune mechanisms to eliminate

virus or virus-infected cells Humoral & cell-mediated immune responses

important for antiviral immunity

Must eliminate both virus & virus-infected cells

Failure to resolve infection leads to; Persistent infection

Late Complications

Humoral immune response acts primarily onextracellular virions/bacteria

Cell-mediated immune responses (T cells) targetvirus-infected cells





Primary and Secondary AntibodyPrimary and Secondary Antibody

ResponsesResponses



VirusVirus--specific T Cell Responses ~specific T Cell Responses ~

CD4 and CD8 T CellsCD4 and CD8 T Cells

Antiviral CD8+ and CD4+ T-cell responses. The three phases of the T-cell immune response (expansion, contraction and memory) areindicated. Antigen-specif ic T cells clonally expand during the first phase in the presence of antigen. Soon after the virus is cleared, the

contraction phase ensues and the number of antigen-specific T cells decreases due to apoptosis. After the contraction phase, the number of virus-specific T cells stabilizes and can be maintained for great lengths of time (the memory phase). Note that, typically, the magnitude of the

CD4+ T-cell response is lower than that of the CD8+ T-cell response, and the contraction phase can be less pronounced than that of CD8+ Tcells. The number of memory CD4+ T cells might decline slowly over time.



Humoral Immune Response

Not all immunogens elicit protective immunity

Best targets usually viral attachment proteins

Capsid proteins of non-enveloped viruses

Envelope glycoproteins of enveloped viruses

Antibody may neutralize free virus particles

Antibody binds virus particles

Blocks binding to cell-surface receptors

Destabilizes virus particles

Antibody opsonizes free virus particles Antibody binds virus particles

Promotes uptake & clearance by macrophages (Fc receptors)

Antibody prevents spread of extracellular virus to other cells

Most important in viremic infections



Antiviral antibodies can impact viral infection in multiple ways.

The antiviral activities of antibodies. a | Activities against free virus (an enveloped virus is shown). Neutralizing antibodies probably actprimarily by binding to the envelope protein (Env) at the surface of the virus and blocking infection (neutralization). They can also trigger effector

systems that can lead to viral clearance, as discussed in the text. b | Activities against infected cells. These activities can be mediated by bothneutralizing and non-neutralizing antibodies. Neutralizing antibodies bind to the same proteins on infected cells as on free virus. Non-neutralizing

antibodies bind to viral proteins that are expressed on infected cells but not, to a significant degree, on free virus particles. Examples includealtered forms of Env protein and certain non-structural (NS) proteins, such as NS1 of dengue virus. The binding of neutralizing and/or non-

neutralizing antibodies to infected cells can lead to clearance of such cells or the inhibition of virus propagationas shown.

Targets for Antiviral AntibodiesTargets for Antiviral Antibodies







Cancer Vaccines

Tumors can be destroyed by cytotoxic T cells or antibody-

dependent cytotoxic mechanisms if the immune system can

identify the tumor as ³nonself´

This is difficult with uninfected cells since the immune response is

generally tolerized toward ³self´ antigens

However, some tumor-specific antigens are expressed by cancer

cells either in a unique context or are antigens that were

expressed prior to but not after the tolerization process. This is

generally because tumor cells are less differentiated than normal

cells.

In addition, tolerance can be broken by especially immunogenic

vaccines

The ³holy grail´ of tumor vaccines is an antigen that is expressed

only by the tumor cells, to which the host is not tolerized





Non-Living Virus Vaccines

No risk of infection by viral agent Generally safe, except in people with allergic reactions

Large amount of antigen elicits protective antibody response

Produced in several ways:

Chemical inactivation (e.g., formalin) of virus Heat inactivation of virus

Purification of components or subunits of viral agent from infected cells

Typically administered with ADJUVANT

Boosts immunogenicity

Influences type of response (TH1 versus TH2, secretory IgA)

Used when wild-type virus:

Cannot be attenuated

Causes recurrent infection

Has oncogenic potential



Live Virus Vaccines

Preparations of viruses limited in ability to cause disease

AVIRULENT ± does not cause human disease (often other species)

ATTENUATED ± deliberately manipulated to become benign

Immunization resembles natural infection

Progresses through normal host response

Humoral, cellular & memory immune responses develop

Immunity generally long-lived

BUT, can revert to virulent form in host

May still be poorly immunogenic

May still be dangerous in immunocompromised individuals

Pregnant women

Infants

Immunosuppressed (chemotherapy, HIV etc.)



Live Virus Vaccines

Live virus vaccines are attenuated because: They are mutants of wild-type virus

They are related viruses with non-human host that share epitopes

They are genetically-engineered to lack virulence properties

Attenuated mutant viruses include: HOST RANGE MUTANTS: Grown in embryonated eggs or tissue

culture cells

TEMPERATURE-SENSITIVE MUTANTS: Grown at non-physiological

temperatures

IMMUNE-SENSITIVE MUTANTS: Grown away from selectivepressures of host immune response

TROPISM-ALTERED MUTANTS: Replicate at benign site, but not

target organ (e.g. Sabin polio vaccine in GI tract but not CNS)

Live-attenuated virus vaccines licensed for measles, mumps,

rubella, VZV, yellow fever & polio



Blind Passage: Most

live attenuated virus

and bacterial vaccines



Live Versus Non-Living Vaccines

Property Live Non-LivingRoute of administration Natural or injection Injection

Cost Low High

Number of doses Single Multiple

Need for adjunvant No YesDuration of immunity Long-term Short-term

Antibody response IgG, IgA IgG

Cell-mediated response Good Poor

Heat lability of vaccine Yes No

Interference Occasional None

Side effects Occasional mild

symptoms

Occasional sore arm

Local versus systemic Both Local

Reversion to virulence Occasionally None



The Future of Vaccines

Molecular biology now applied to vaccine design

New live vaccines genetically engineered to

inactivate/delete virulence genes Replaces random attenuation by cell culture passage

Many new types of vaccines now being developed:

SUBUNIT VACCINES (not technically gene therapy)

HYBRID VIRUS VACCINES

REPLICON VACCINES

DNA VACCINES





Subunit Protein Vaccines

Genes for immunogenic proteins cloned into bacterial &eukaryotic expression vectors which produce protein in vitro:

Identifying appropriate subunit or peptide immunogen to elicit

protective antibody & ideally CTL

Present antigen in correct conformation

Examples include:

HBV surface antigen (in use)

HIV gp120

Influenza virus hemagglutinin

Papillomavirus virus-like particles (VLP; in use)

With viruses, single proteins can make particles that bud

from cells (VLP) that can use class I and class II pathways



Hybrid Virus & Replicon Vaccines

Genes from infectious agents that cannot be attenuatedinserted into ³safe´ viruses:

CHIMERIC VIRUSES: Combined genomes from related virulent &

attenuated viruses

YFV 17D-based vaccines for dengue, West Nile & Japanese

encephalitis virus

VIRUS VECTORS: Attenuated virus engineered to express

immunogenic gene from pathogenic virus

Canarypox, retrovirus & alphavirus vectors

Replicons - virus particles capable of only one round of infection

Essential gene(s) deleted from genome

Added back in trans to make virus particles in cell culture



Chimeric RNA virus (Acambis ³Chimeravax´)

cDNA clone of 17D Yellow fever virus vaccine with C, prM and E of

Dengue, Japanese encephalitis or West Nile virus substituted

Viral

Immunogens



26S

Structural

Genomic

Foreignprotein

26S

Non-structural

RNA virus vector expressing heterologous

immunogen

More like natural infection but possibility for virulence

Alphaviruses



26SGenomic

ImmunogenNon-structural

26S

Capsid

Alphavirus replicon expressing heterologous Alphavirus replicon expressing heterologous

immunogen (limits potential for virulence)immunogen (limits potential for virulence)

26S

E3/E2/E1



2

Alphavirus Replicon Vectors Alphavirus Replicon Vectors

26SGenomic

Non-structural

26S

Capsid

26S

E3/E2/E1

Immunogen

Alphaviruses

natrually

target

dendritic

cells (APCs)





DNA Vaccines

Great potential for immunization against infectious agents requiring T cell & antibody

responses

Gene of protein eliciting immune response cloned into eukaryotic expression vector

Naked DNA injected into muscle or skin

DNA taken up by cells & gene expressed

Protein produced and presented to immune system

Very easy to design & produce

Extremely safe, no possibility of reversion to virulence

Have many similar drawbacks to other non-living vaccines (limited immunogenicity, require

adjuvants)

However, bacterial DNA (plasmid amplified in bacteria) is a natural adjuvant for Toll-like

receptor 9, an innate immunity stimulating molecule



Plasmid

contains general

eukaryotic

promoter (e.g.,

cytomegalovirus

promoter in

pcDNA3.1) that

is transcribed in

most

mammalian cells



Immunogen determines route of presentation e.g.,

class I (cytoplasmic) vs. class II (secreted)



Clinical trials for plasmid-based cancer vaccines



Gene Therapy Adjuvants Adjuvant can be protein delivered with live or killed vaccine

For gene therapy, adjuvant can be delivered by a vector:Virus

Replicon

Bacterium

Plasmid

Or, adjuvant can be the nucleic acid itself delivered with another vaccine (usually

killed vaccine)

Adjuvant protein and/or nucleic acid is utilized to increase the response of host

cells such that immunization with vaccine resembles or is more stimulating than

natural agent infection. Examples:

Mip3-alpha ± chemokine attracting immature dendritic cells

IFN-gamma ± cytokine skewing towards TH1 immunityIL-12 ± cytokine promoting TH1 and mucosal antibody

CpG DNA ± elicits cytokine response like pathogen

Virus RNA ± elicits cytokine response like pathogen

CD86 - co-stimulatory molecule can be supplied, required for

naïve T cell activation

Ubiquitin ± proteasome targeting molecule, enhances Ag processing



Adjuvants

26SGenomic

Cytokine (e.g.,IFN-g,

IL-12)

Non-structural

26S

Capsid

Alphavirus replicon expressing Alphavirus replicon expressing

adjuvantadjuvant

26S

E3/E2/E1



Virus Vaccines Licensed in U.S.

Hepatitis B virus Parenteral, recombinant protein

Measles Parenteral, live, booster 4-6 yrs

Mumps Parenteral, live, booster 4-6 yrs

Poliovirus Parenteral, killed

Rubella Parenteral, live

Varicella Parenteral, live

Universal

childhood

vaccines



Influenza A & B virus Elderly Parenteral, annual, killed

Hepatitis A virus Travelers Parenteral, killed

Japanese encephalitis virus Travelers Parenteral, killed

Yellow fever virus Travelers Parenteral, live

Rabies High-risk Prophylactic &

therapeutic , killed

Smallpox High-risk Intradermal, live

Rotavirus Children Live, cow virus

Human Papilloma virus (3 dose) Females Intramuscular, Recombinant

Virus-Like Particle (no DNA)

Virus Vaccines Licensed in U.S.



Bacteria as vaccines/vectors

Killed/Subunit ± DTaP , anthrax, meningococcal meningitis,

Live attenuated ± Mycobac terium bov is cow bacterium (BCG), Salmonella

t yphimurium Ty21a, CVD, Vi bri o cholera 103-HgR

Expression of heterologous antigen ± S. t yphimurium, Listeria

monocy t og enes, Bac illus ant hrac is

Plasmid delivery ± S hi g ella s p., Listeria s p. Some intracellular bacteria

target dendritic cells and can deliver plasmids to the APCs

Advantages: can give orally for mucosal immunity, sometimes longterm antigen expression

Disadvantages: much more complex than viruses, attenuation

mechanisms less well understood and may have unexpected long

term consequences for vaccinees

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History of Vaccines 8667

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